The high degree of infectiousness and fast reproduction cycle of viruses within host organisms make viruses a nuisance and a health hazard. There is no simple treatment of viral diseases. Viruses are not susceptible to antibiotics. The only available treatment of viral diseases is chemotherapy utilizing viral replication inhibitors in host cells The Merck Manual, 170 (1982), 14th Ed.). Examples of these chemical agents are idoxuridine, acyclovir, ribavirin, vidarabine, gancyclovir, adenine arabinoside (ABA-A) and AZT. These, and other viral replication inhibitors, however, are cytotoxic, hepatotoxic, neurotoxic, nephrotoxic and teratogenic (Virus Diseases, 1-6 (1978), Crown Publishers, N.Y.).
Human immunodeficiency virus (HIV) infections known as acquired immunodeficiency syndrome (AIDS) presently constitute a worldwide health hazard. HIV infections are almost always fatal due to a weakened immunoresistance, leading to opportunistic infections, malignancies and neurologic lesions. There are few effective treatments for AIDS other than the treatment of the opportunistic infections, neoplasms and other complications. Available cytostatic (AZT) and antiviral (acyclovir) drugs are extremely toxic and cause severe adverse reactions. Novel classes of protease inhibitors have not been satisfactorily studied over the long term to assure continued efficacy and to assess long term side effects. Thus it would be highly desirable to have available an effective and yet nontoxic treatment of viral diseases, in particular, AIDS.
Herpes simplex virus type-1 and 2 are also widespread infections. They may occur in AIDS patients as one of the opportunistic infections. Type-1 HSVstrain (HSV-1) commonly causes herpes labialism located on a lip, and keratitis, an inflammation of the cornea. Type-2 HSV is usually located on or around the genital area and is generally transmitted primarily by direct contact with herpetic sores or lesions. HSV-2 has been related to the development of uterine cancer. Herpes simplex virus is very infectious and is rapidly and easily transferable by contact. There is no specific therapy for this extremely painful viral infection. Current treatment of HSV infections is limited primarily to systemic administration of the above-mentioned antiviral drugs with corresponding adverse side affects. The antiviral agents used for treatment are non-selective inhibitors of HSV replication affecting the replication of normal cells as well. Therefore, when used in doses large enough to inactivate all of the active herpes viruses dormant in the sensory ganglia, these compounds may also be highly disruptive to host cell DNA replication. Thus, it would be advantageous to have available non-toxic treatment of HSV infections.
Cytomegalovirus (CMV), a dangerous co-infection of HIV, is a subgroup of highly infectious viruses having the propensity for remaining latent in man. CMVs are very common among the adult population and as many as 90% of adults have been exposed to and experienced CMV infections. CMVs are normally present in body liquids such as blood, lymph, saliva, urine, feces, milk, etc. CMV infections may cause abortion, stillbirth, postnatal death from hemorrhage, anemia, and severe hepatic or CNS damage. Particularly dangerous are CMV infections afflicting AIDS patients, where CMV may cause pulmonary, gastrointestinal or renal complications. There is no specific therapy for CMV infection. Unlike many other viruses, CMV is resistant to acyclovir, and to other known antiviral drugs. There is a great need to provide effective treatments for CMV infections.
Recently, it was discovered that agents that bind and/or inhibit the assembly or formation of microtubules are effective in inhibiting or preventing certain cancers. This is the subject of U.S. Ser. Nos. 08/655,267 and 08/833,272 filed on Jun. 4, 1996 and Apr. 3, 1997 respectively. The disclosures of both applications are herein expressly incorporated by reference in their entirety. Ketone diiodo thyronine analogues useful for treating cancer are the subject of U.S. Ser. No. 08/956,711 filed Oct. 23, 1997. The disclosure of this application is also herein expressly incorporated by reference in its entirety.
New classes of therapeutic agents providing new points of intervention for inhibiting or preventing viral infection and replication would be highly useful. It has been discovered that agents that bind and/or inhibit the assembly or formation of microtubules are effective in inhibiting or preventing viral infection and/or replication.